Hepatitis C virus (HCV) infection is a major cause of morbidity and mortality. Injection drug users have the highest prevalence of HCV infection among all populations in the U.S. at risk. We will study prospectively the natural history of HCV infection among all populations in the U.S. at risk. We will study prospectively the natural history of HCV infection in a cohort of drug users with or at risk for HIV infection. Subjects will be recruited from among participants already enrolled in a large longitudinal study of the natural history of HIV infection in drug users. We will, therefore, be able to take advantage of the large and complex sets of data being collected in that study, and we will be able to link new data that will be collecting on the natural history of HCV infection with those data. Participants will have detailed standardized interviews on demographics, medical history, sexual and drug use behaviors, HIV and immunological testing, and testing for HCV infection, including quantitative HCV RNA levels, including quantitative HCV RNA levels, HCV genotyping, anti-HCV antibodies and, in a subset of participants, HCV sequencing. Persons found to have HCV infection will be referred to the study hepatologist to be evaluated for liver disease and they will be offered standard medical therapy for their HCV infection. Our aims are to determine 1) the effects of HIV infection and its associated immunodeficiency, HCV genotype, and drug use behaviors on HCV viral load and progression of liver disease, 2) the effects of HIV infection and immunodeficiency on response to therapy for HCV infection, 3) the effects of highly active anti-retroviral therapy and control of HIV viral load on the natural history of HCV infection, and 4) whether genetic diversity of HCV is facilitated by immunodeficiency.